Small fiber neuropathy (SFN) is a disorder characterized by degeneration or dysfunction of small diameter unmyelinated nerve fibers in the peripheral nervous system (1, 2). Patients with SFN have sensory defects with a variety of symptoms, including loss of sensation or chronic pain. Despite its prevalence, the etiology of SFN is poorly understood and there are currently no effective treatments. Since the initial stages of SFN commonly involve degeneration of nerve terminals without loss of neuronal cell bodies (3), we wondered if delivery of therapeutic agents at the target of innervation, i.e. the skin, would be an effective non-invasive approach that could minimize the side effects commonly observed with systemic drug delivery methods.
When considering molecules that could be used in this fashion, we focused on neurotrophic factors, which have been viewed as potentially useful therapeutic agents in the treatment of peripheral neuropathies because they regulate the survival and function of peripheral nerves during development (4, 5). In addition, decreases in expression of certain trophic factors have been observed in multiple models of peripheral neuropathy (6, 7) suggesting that low levels of these factors may be involved in disease etiology. One of these trophic factors, GDNF, is necessary for proper development and survival of small diameter unmyelinated nerve fibers (5, 8). In early postnatal life, a large proportion of developing unmyelinated nerve fibers switch from dependence on nerve growth factor (NGF) to dependence on GDNF (5). This transition coincides with a gradual decrease in expression of the NGF receptor (TrkA) with a corresponding increase in the expression of GDNF family receptors by dorsal root ganglion sensory neurons (4). Based on the known roles of the GDNF pathway in peripheral nerve development and function and the pattern of expression of GDNF family ligands and receptors, we decided to test if application of GDNF receptor ligands to the skin could be used to treat SFN. To address this question, we used two mouse models of SFN arising from different pathogenic processes. In one model, progressive SFN results from disruption of non-myelinating Schwann cell (NMSC) function (6). In the other, rapid onset SFN is caused by treatment with a toxin (resiniferatoxin, RTX) that activates TRPV1 channels in c-fiber nerve terminals, inducing loss of unmyelinated fiber nerve terminals in the skin and loss of thermal nociception (9). Here we show that topical delivery of GDNF receptor ligands to affected skin areas is sufficient to prevent degeneration and maintain sensory function in both types of SFN. In addition, we demonstrate that the non-peptidyl GFRα1 agonist XIB4035 and related quinolines are capable of providing trophic support to peripheral nerves in vivo and thus are useful therapeutic agents in the treatment of SFN.
Use of N4-{7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl}-N1,N1-diethyl-pentane-1,4-diamine (XIB4035), also known as 7-chloro-2-(o-chlorostyryl)-4-[4diethylamino-1-methylbutyl]aminoquiinoline phosphate), and 2-(2-Chlorostyryl)-4-(delta-diethylamino-alpha-methylbutylamino)-7-chloroquinazoline (CAS RN 57942-32-2; CAS 10023-54-8) has been described, e.g. Tokugawa et al., Neurochem Intnl 2003, 42, 81-86; WO01003649; and JP 2008-230974.